Portal de Periódicos da CAPES

Life-threatening viral disease in a novel form of autosomal recessive IFNAR2 deficiency in the Arctic

2022; Rockefeller University Press; Volume: 219; Issue: 6 Linguagem: Inglês

10.1084/jem.20212427

1540-9538

C.J. Duncan, Morten Kelder Skouboe, Sophie Howarth, Anne Kruse Hollensen, Rui Chen, Malene Landbo Børresen, Benjamin Thompson, Jarmila Stremenova Spegarova, Catherine F. Hatton, Frederik Filip Stæger, Mette K. Andersen, John Whittaker, Søren R. Paludan, Sofie E. Jørgensen, Martin K. Thomsen, Jacob Giehm Mikkelsen, Carsten Heilmann, Daniela Buhaş, Nina Friesgaard Øbro, Jakob Thaning Bay, Hanne Vibeke Marquart, M. Teresa de la Morena, Joseph Klejka, Matthew Hirschfeld, L. Borgwardt, Isabel Forss, Tania Nicole Masmas, Anja Poulsen, Francisco Noya, Guy A. Rouleau, Torben Hansen, Sirui Zhou, Anders Albrechtsen, Reza Alizadehfar, Eric J. Allenspach, Sophie Hambleton, Trine H. Mogensen,

Immunodeficiency and Autoimmune Disorders

Type I interferons (IFN-I) play a critical role in human antiviral immunity, as demonstrated by the exceptionally rare deleterious variants of IFNAR1 or IFNAR2. We investigated five children from Greenland, Canada, and Alaska presenting with viral diseases, including life-threatening COVID-19 or influenza, in addition to meningoencephalitis and/or hemophagocytic lymphohistiocytosis following live-attenuated viral vaccination. The affected individuals bore the same homozygous IFNAR2 c.157T>C, p.Ser53Pro missense variant. Although absent from reference databases, p.Ser53Pro occurred with a minor allele frequency of 0.034 in their Inuit ancestry. The serine to proline substitution prevented cell surface expression of IFNAR2 protein, small amounts of which persisted intracellularly in an aberrantly glycosylated state. Cells exclusively expressing the p.Ser53Pro variant lacked responses to recombinant IFN-I and displayed heightened vulnerability to multiple viruses in vitro—a phenotype rescued by wild-type IFNAR2 complementation. This novel form of autosomal recessive IFNAR2 deficiency reinforces the essential role of IFN-I in viral immunity. Further studies are warranted to assess the need for population screening.